Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid cell lineage neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia. Annual report summary Lymphoma section Malignancies of B and T lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal lymphoid cells are misdirected, leading to the activation of cancer-causing genes, termed oncogenes. We previously established that mice develop a spectrum of B cell lineage tumors with many parallels to similar human neoplasms. Our studies are directed first at determining how similar the tumors of the two species are so that we can understand how to develop better mouse models for human neoplasms. Relevant models would provide opportunities for understanding the mechanisms driving diseases as well as for developing new approaches to diagnosis, treatment and possibly prevention. Mechanisms known to contribute to tumor development in many species include activation of oncogenes, inhibition of tumor suppressor genes (TSG) and mutation of DNA repair genes. A second major purpose of our studies then is to determine if and how these mechanisms also contribute to mouse lymphoid neoplasms. Finally, we believe the knowing how mutant or abnormally expressed genes contribute to tumorigenesis will direct us to important insights into how they contribute to normal T and B cell biology. These directions have led us to study a spectrum of mice that develop T or B cell lymphomas either spontaneously or following genetic manipulations that silence or aberrantly activate selected genes with much of the work being done in collaborations with scientists at the NIH and in academia. We utilized cross-species gene expression profiling to identify candidate genes for involvement in human B cell lineage neoplasms. The study was based on global gene expression profiles of diffuse large B cell (DLBCL)-like tumors that arose in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. We identified 60 concordantly deregulated genes in common to the mouse and human lymphomas, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting previous studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the mouse filter for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in mouse models of solid human cancers, but its potential for assessing tumor development and new interventions in mouse models of human blood cancers such as multiple myeloma (MM) had not been demonstrated. We used two models of plasmacytoma (PCT) development in mice bearing Myc and IL6 transgenes (frequently employed models of human multiple myeloma (MM)). These studies showed that FDG-PET/CT could provide an important research tool for assessing PCT development in a serial, reproducible and stage- and lesion-specific manner. We also showed that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational drugs such as the proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated.. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma. Cbl is an an oncogene originally discovered by our laboratory. Studies in humans and mice showed that different mutations contribute to the development of B cell lymphomas as well myeloproliferative (MPD) diseases. Mice with mutations in a particular portion of the gene develop a myeloproliferative disease similar to that found in humans with essentially the same mutation. Both diseases are associated with increased activity of tyrosine kinases, enzymes that can cause unregulated cell growth when overly active. Our studies were directed at understanding if disantinib, an inhibitor of some of these enzymes, would be an effective therapy for the mouse disease. Surprisingly we found that dasatinib did not provide an effective therapy for Cbl mutant mice since it did not suppress any of the hematopoietic lineages that promote MPD development. Thus we conclude that dasatinib may not be an appropriate therapy for leukemia patients with c-Cbl mutations T cell activation must be controlled to prevent the development of inflammatory and neoplastic diseases. Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been examined. Studies of T cell showed that mice deficient in expression of either of the genes exhibited a variety of abnormalities, many non-overlapping of both conventional and regulatory T cell subsets. Unexpected, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis in T cells as well as B cells. Finally, we continue to be active in efforts to improve the classification systems for mouse hematopoietic neoplasms as they relate to similar human neoplasms. It is important for pathologists to be able to discriminate between hematopoietic neoplasms and non-malignant reactive lesions in the mouse and we have developed guidelines for making these determinations.